Maternal separation has long been associated with depressive illness. In some species of primates as well as guinea pigs, infants exhibit a 2-stage, active /passive response during maternal separation. The second stage of separation (termed "despair" in primates) has been a long-standing model for the study of depressive illness. Further, the "stress diathesis" model of depression proposes that the occurrence of early maternal separation and related stressors enhances vulnerability to later depression through a process that involves sensitization of central processes mediating stress responses. In guinea pigs, proinflammatory cytokines appear to be important mediators of the passive behavioral response, and sensitization of the response occurs when pups are separated on consecutive days. Studies proposed here will examine the role of proinflammatory factors in the sensitization process (Specific Aim 1) by attempting to block the behavioral sensitization as well as related changes in core temperature and central and peripheral proinflammatory markers with the anti-inflammatory cytokine, Interleukin-10. Under Specific Aim 2, studies will examine whether activation of a proinflammatory cascade or repeated maternal separation during the preweaning period will enhance passive responses, core temperature changes, central and peripheral proinflammatory markers, and plasma cortisol levels during a period of social isolation during the periadolescent period. The proposed work meets the objectives of the AREA mechanism by providing meaningful research experience to undergraduates who will participate in all phases of the experimental work. PUBLIC HEALTH RELEVANCE: The relevance of the work is that it would: (1) provide a potential means of incorporating a long-standing animal model of depression (the passive "despair" stage of maternal separation) with current notions of the role of proinflammatory factors in depressive illness;and (2) suggest a novel way in which proinflammatory factors might take part in the sensitization process central to the stress-diathesis model of depression.